Deep hypothermia, which is used during thoracic aortic surgery for neuroprotection, is associated with coagulation abnormalities in animal and in vitro models. However, there is a paucity of data regarding the impact of deep hypothermia duration on perioperative bleeding. The objective of the current study was to examine the relationship between the duration of deep hypothermia and perioperative bleeding. A retrospective review of 507 consecutive thoracic aortic surgery patients who had surgery with deep hypothermic circulatory arrest was performed. The degree of bleeding and coagulopathy was estimated using perioperative transfusion. Log linear modeling with Poisson regression was used to analyze the relationship between deep hypothermia duration and perioperative bleeding, while controlling for other preselected variables. There was a significant association between deep hypothermia duration and RBC transfusion (P = 0.001). There was no significant association between deep hypothermia duration and FFP and platelet transfusion (P = 0.18 and P = 0.06). The association between deep hypothermia duration and the amount of bleeding (RBC transfusion) was dependent on total CPB time. In general, for shorter CPB times (approximately 120 to 180 minutes) there was an upward sloping line or positive relationship between deep hypothermia duration and bleeding. However, for cases with longer CPB times (300 to 360 minutes), there was no such relationship. The relationship between deep hypothermia duration and perioperative bleeding is dependent on CPB time. For surgeries with short CPB times (120 to 180 minutes), prolonged deep hypothermia is associated with increased post-operative bleeding, as estimated by RBC transfusion. For cases with longer CPB times (300 to 360 minutes), there appears to be no relationship.

As early as the 1950s, cardiac surgeons described the coagulopathy that occurs after profoundly lowering body temperature for surgery. [1] Today deep hypothermia is widely utilized as a cerebral protection strategy during periods of requisite circulatory arrest in cardiac surgery. Although other cerebral protection strategies have been utilized, deep hypothermia remains the standard in clinical practice. [2],[3]

Perfusionists often use institutional or surgeon specific protocols for cooling, rewarming, and initiating circulatory arrest during thoracic aortic surgery. However, in our experience these practices remain highly variable. The result is that patients who have relatively similar surgical procedures and cardiopulmonary bypass (CPB) times spend differing amounts of time under deep hypothermia. Recent literature suggests that thoracic aortic surgery with circulatory arrest can also be performed under less profound hypothermia with comparable rates of neurologic injury. [4],[5] This raises the question of whether the negative effects of deep hypothermia outweigh its benefits. One possible negative effect of prolonged deep hypothermia is coagulopathy, which results in increased transfusion of allogenic blood products. The coagulopathy that occurs during hypothermia is due to alterations in both clotting factors and platelets. As blood temperature is reduced both the prothrombin time (PT) and activated partial thromboplastin time (aPTT) become prolonged in an exponential pattern. [6],[7] This is due to inhibition of the enzymes in the coagulation cascade at low temperatures. When coagulation is assessed using thromboelastometry or thromboelastography, hypothermia prolongs the coagulation time and clot formation time in whole blood. [8],[9],[10] In animal models, platelet counts fall significantly during deep hypothermia. This is believed to be due to a reversible sequestration of platelets in the liver. After return to normothermia, it appears that platelet counts return to normal and platelet lifespan is not shortened. [11] However, prolonged storage of platelets at low temperatures (below 22 degrees) has been known for years to shorten platelet lifespan. [12] Animal models have also shown that platelet function is decreased during hypothermia because of decreased thromboxane production. This effect also appears to be reversible with the return of normothermia. [13] Despite the knowledge gained from previous animal studies and in vitro studies, the relationship between deep hypothermia duration and perioperative bleeding after major cardiothoracic surgery remains poorly understood. The aim of the current study was to test the hypothesis that the portion of CPB that occurs under deep hypothermia is independently associated with perioperative bleeding and coagulopathy. Allogenic transfusion was used as a proxy to estimate the degree of perioperative bleeding and coagulopathy.

Materials and Methods

Data CollectionOur institutional review board approved the study and waived the requirement for informed consent. A retrospective data review of all consecutive patients that underwent thoracic aortic surgery under deep hypothermic circulatory arrest (DHCA) between July 1 st 2002 and December 31 st 2007 was performed. All cardiac surgery cases performed during the study period were reviewed in order to identify those subjects who required DHCA. Only patients greater than 18 years of age were included. There were no other exclusion criteria. No patient was counted more than once in the analysis. All data were collected and stored in a HIPAA (Health Insurance Portability and Accountability Act) and institutionally compliant manner.

For each subject multiple preoperative and intraoperative variables were recorded in a database. These included the following: gender, age, weight, American Society of Anesthesiologists (ASA) Physical Status Score, day of admission for surgery (DAS) or inpatient status, year of surgery, operating surgeon, emergency surgery, surgical diagnosis, specific operation performed, history of previous sternotomy or left thoracotomy (reoperation), history of hypertension, history of dyslipidemia, history of diabetes, history of cerebral vascular disease, history of ischemic heart disease, history of hemodialysis, baseline creatinine >2.0 mg/dl, history of chronic obstructive pulmonary disease (COPD), history of congestive heart failure (CHF), preoperative international normalized ratio (INR), preoperative activated partial thromboplastin time (aPTT), preoperative hematocrit, preoperative platelet count, preoperative clopidogrel use, and preoperative aspirin use. The following intraoperative variables were collected: surgical procedure, surgical incision, CPB time, deep hypothermic circulatory arrest time (DHCA time), lowest esophageal temperature, total deep hypothermia time, aprotinin administration, and epsilon amino-caproic acid administration. We also recorded all blood products that were administered during the perioperative period, which included the following: red blood cells (RBCs), fresh frozen plasma (FFP), platelet apheresis unit equivalents (Plat), and cryoprecipitate pools (Cryo).

DefinitionsThe perioperative period was defined in our study as intraoperative time and the 48 hours after. Congestive heart failure was defined as a history of either systolic or diastolic heart failure with confirmatory left ventricular echocardiographic findings. Ischemic heart disease was defined as any of the following: Q wave on previous electrocardiogram, previous nitrate use for chest pain, previous coronary artery bypass grafting (CABG) or percutaneous intervention (PCI), previous positive noninvasive test indicating ischemia, or previous non-Q wave myocardial infarction. Cerebral vascular disease was defined as a previous cerebral vascular accident (CVA), transient ischemic attack (TIA), or carotid endarterectomy. Hypertension was defined as a history of systolic or diastolic hypertension requiring the use of antihypertensive medication. Dyslipidemia was defined as a history of hypercholesterolemia or hypertriglyceridemia requiring the use of lipid lowering medication. Aspirin use and clopidogrel use were identified in the preoperative medication list.

Blood product transfusion was used as a proxy to estimate the degree of perioperative bleeding and coagulopathy. One platelet apheresis unit equivalent was defined as either a single unit of apheresis platelets or six single donor units. In our institution, these provide approximately an equal number of total platelets. For this reason, some patients in the study are described as having received a fraction of a platelet apheresis unit equivalent (e.g., patient received 5 single donor units = 0.83 apheresis equivalents). One cryoprecipitate pool was defined as 10 individual cryoprecipitate units. One red blood cell unit was a single donor unit of packed red blood cells (approximately 250 ml). One unit of FFP was a single donor unit of FFP (approximately 250 ml).

CPB time in our study reflects the total CPB time added to any complete circulatory arrest time and any selective cerebral perfusion time. In our electronic medical record system, total CPB time is recorded in this way. Total deep hypothermia time was the total time below 20 °C as recorded by an esophageal temperature probe.

The Deep Hypothermia ProportionTotal CPB time is a well-established predictor of perioperative bleeding, coagulopathy, and transfusion. Because total deep hypothermia time was closely related to total CPB time, an additional variable called the deep hypothermia proportion was created. In order to calculate the deep hypothermia proportion we divided the total deep hypothermia time by the total CPB time for each subject. This allowed for comparison of bleeding in cases with similar CPB times, but differing proportions of hypothermia.

Surgical CasesSurgical cases were identified from an electronic anesthesia database. All consecutive adult cardiothoracic surgery cases that required deep hypothermia during the five-year study period were included. There were no exclusion criteria. The surgical cases in the study included all types of aortic replacement surgery that required deep hypothermia. Specifically this included ascending aortic replacements (both valve sparing and valve replacing), total arch replacements, hemi-arch replacements, and descending aorta replacements. Combination procedures were also included such as ascending aorta replacement with total arch replacement and ascending aorta replacement with coronary artery bypass. All surgeries were performed in a single center by one of 15 surgeons. A single surgeon performed half the procedures. Procedures were classified as either isolated descending aortic replacements or ascending aorta and arch procedures.

Transfusion Decisions and PracticesDuring the study period no specific intraoperative or postoperative algorithm was used to guide transfusion of blood products. Individual anesthesiologists and surgeons made decisions about transfusion during the surgical procedure. During the postoperative period either intensivists or surgeons made decisions about transfusion.

Statistical MethodsInitially the transfusion data were examined for all subjects. Median values as well as minimum and maximum values were then calculated for each blood product to reflect the overall distribution of transfusion in the cohort. We then performed a univariate test of association between total deep hypothermia time and the primary outcomes variables of interest: transfused units of RBCs, FFP, and platelets. Spearman correlation coefficients were used to evaluate this relationship.

Multivariate AnalysisBecause the majority of subjects received none or a small amount of blood product transfusion, the distributions of transfusion were highly skewed. We rounded the units of RBCs, platelets, and FFP needed for each subject to the nearest integer and used log linear modeling with Poisson regression to test whether the deep hypothermia proportion was associated with an increased number of transfused blood products. The exponential of the parameter estimates from the log linear model was the relative amount of blood product required compared to the reference point. The model controlled for other covariates that were preselected by the authors and included age, weight, inpatient status, gender, race, year of surgery, surgeon, CPB time, preoperative INR, preoperative aPTT, preoperative hematocrit (hct), preoperative platelet count, emergency status, ASA physical status, descending aorta replacement versus other aortic procedure, reoperation, preoperative intrathoracic infection, lowest esophageal temperature, intraoperative aprotinin use, intraoperative epsilon amino caproic acid use, preoperative aspirin use, preoperative beta blocker use, and preoperative clopidogrel use. Furthermore, the model tested the interaction between the CPB time and the proportion of deep hypothermia under CPB to assess whether the effect of deep hypothermia differed depending on the duration of CPB. A Bonferroni correction was used to account for the fact that three different blood products were studied as outcome variables. Based on this correction, a P value of 0.01 was considered to be statistically significant. Ninetynine percent confidence intervals were presented for parameter estimates.

Results

There were 507 patients who met study enrollment criteria. Patient characteristics including demographic data, medical history, surgical variables, and preoperative medications are shown in [Table 1] with median, minimum, and maximum values or number and percentage listed as appropriate.

In [Table 2], the distribution of transfusion for the cohort is shown by CPB time. Median, minimum, and maximum values are described for all blood products that were examined in the study. Total RBC units transfused ranged from 0 to 42 with the median number of units transfused tending to increase with total CPB time. Total platelet apheresis unit equivalents ranged from 0 to 6.83 with the median number of units transfused tending to increase with total CPB time. Total FFP units ranged from 0 to 21 with the median number of units transfused tending to increase with total CPB time. Total cyroprecipitate pools transfused ranged from 0 to 5. Nineteen patients (3.7%) required re-exploration for a bleeding complication.

Spearman correlations revealed that total deep hypothermia duration was positively associated with perioperative transfusion of RBCs, platelets, and FFP when other variables were not controlled for (all P < 0.01).

In the multivariate models, total CPB time and total deep hypothermia time were associated with perioperative transfusion of RBCs, platelets, and FFP (all P < 0.01). RBC transfusion was associated with the deep hypothermia proportion (P = 0.003). Platelet and FFP transfusion were not associated with the deep hypothermia proportion (P = 0.06 and P = 0.18, respectively), but platelet transfusions nearly reached significance (P = 0.06). Further, the interaction term between the deep hypothermia proportion and CPB time was significant for RBC transfusion (P = 0.006). This suggested that the impact of deep hypothermia on the amount of RBCs transfused was highly dependent on the duration of CPB. In [Figure 1], the five panels represent CBP time in minutes. In each panel, the x-axis is the deep hypothermia proportion and the y-axis is the relative amount of RBC required compared to a reference point, which was chosen to be 30 minutes of deep hypothermia. For example, a deep hypothermia proportion of 60% in a CPB of 120 min is equivalent to 72 minutes of deep hypothermia, and the relative amount of RBC required is approximately 1.5 times of that required for a subject whose deep hypothermia time was only 30 minutes. In general, for shorter CPB times (approximately 100 to 200 minutes) there is an upward sloping line or positive relationship between the deep hypothermia proportion and RBC transfusion. However, for cases with longer CPB times (300 to 400 minutes), this line becomes flat and the impact of the deep hypothermia proportion on bleeding is negated.

Figure 1: The five panels show different CPB times. In each panel the deep hypothermia proportion is represented on the X-axis. The y-axis represents units of RBCs transfused. The curves represent the relative amount of RBC required as compared to a reference point, which was chosen to be 30 minutes of deep hypothermia

Other preoperative and intraoperative variables that were associated with transfusion in the multivariate models are listed in [Table 3]. The variables that were associated with RBC transfusion included age, low body weight, preoperative hct, descending aorta replacement, and reoperation (all P < 0.01). Variables that were associated with platelet transfusion included age, preoperative platelet count, emergency surgery, descending aorta replacement, and reoperation (all P < 0.01). Variables that were associated with FFP transfusion included age, low body weight, reoperation, and descending aorta replacement (all P < 0.01). Some surgeons were associated with higher rates of transfusion revealing some heterogeneity in clinical practice. The year of surgery had no pattern of association with transfusion.

In a cohort of 507 consecutive patients who had thoracic aortic surgery with deep hypothermic circulatory arrest, we examined the relationship between deep hypothermia time and perioperative bleeding and coagulopathy. Perioperative transfusion of blood products was used as a proxy to estimate the degree of bleeding and coagulopathy. For surgeries with shorter CPB times (120 to 180 minutes), the percentage of time under deep hypothermia was associated with perioperative RBC transfusion. However, for surgeries with longer CPB times (300 to 360 minutes) it was not. Variables other than CPB time and deep hypothermia time that were associated with bleeding in our multivariate analyses included: age, low body weight, reoperation, descending aorta replacement, emergency surgery, low preoperative hct, and low preoperative platelet count.

Cardiac surgery consumes a large portion of banked blood products. Thoracic aortic surgery in particular is associated with large transfusion requirements and occasionally massive transfusion. In a study of 168 consecutive patients having thoracic aortic surgery under deep hypothermia 6 variables accounted for 42% of transfusion variation. These were: age, preoperative hemoglobin, body weight, CPB time, emergency status, and resternotomy. [14] To our knowledge the relationship between deep hypothermia duration and perioperative bleeding in cardiac surgery remains poorly understood. Numerous in vitro and animal studies have described mechanisms by which deep hypothermia can lead to coagulopathy. [15],[16],[17],[18] However, the impact of hypothermia duration on bleeding in clinical practice remains uncertain and no randomized trials to our knowledge have compared bleeding complications in patients having aortic surgery under deep hypothermia with those having surgery under mild or moderate hypothermia.

Recent reports suggest that thoracic aortic surgery can be performed under less profound hypothermia with low rates of neurologic injury. [4],[5] If these findings are corroborated, the risk to benefit ratio of deep hypothermia may come into question, particularly for cases with shorter circulatory arrest times or in those with anterograde selective cerebral perfusion. A putative risk of prolonged deep hypothermia is worsened coagulopathy and bleeding. In our study, for surgeries with short CPB times, prolonged deep hypothermia was associated with increased bleeding and transfusion of RBCs. In our experience there is a high degree of variability in the way patients are cooled and rewarmed during circulatory arrest cases. In particular patients are rewarmed at different rates. This may be due to the technical challenges of rewarming at a consistent rate or preferences of the surgeon or the perfusionist. There is some evidence that rapid rewarming may worsen brain injury and for this reason some perfusionists and surgeons rewarm more slowly, prolonging deep hypothermia time. [18],[19] Also surgeons take a variable amount of time to complete anastamoses depending upon their experience and skill, which can prolong deep hypothermia time. For an experienced surgeon, performing an ascending aortic replacement with a brief anticipated period of circulatory arrest, mild hypothermia may eventually prove to be the optimal strategy in terms of balancing the risk of neurologic injury with the risk of postoperative bleeding. Our data suggest that in short cases a high percentage of time under deep hypothermia leads to significantly more bleeding. However, for more complex aortic replacements or for less experienced surgeons (longer CPB time), a high percentage of deep hypothermia time may be the safest strategy. Our data suggest that in these cases prolonged deep hypothermia doesn't increase the risk for bleeding and it probably provides better cerebral protection. We postulate that in longer cases, the process of CPB itself is the main determinant of coagulopathy and the effects of deep hypothermia on bleeding become relatively unimportant.

A major limitation of our study is its retrospective design, which makes it more prone to inaccuracies in data collection and bias. Also, there was no suitable control group to compare against because almost all thoracic aortic replacements in our center are performed under deep hypothermia. Another limitation of our study is that we used transfusion of blood products during surgery and the subsequent 48 hours as a surrogate for perioperative bleeding and coagulopathy. Unfortunately, postopearative chest tube drainage was not available in our electronic database. Additionally, not all physicians use identical transfusion thresholds and some patients in the study may have been transfused more than others simply because of different physician practices or biases. We did find that some surgeons were associated with increased blood product transfusion in the multivariate model revealing heterogeneity in clinical practice or a varying level of surgical skill. Finally, not all blood product units contain an equal volume or an equal amount of product. This may lead to imprecise comparisons between subjects who received an equal number of units. Despite these limitations, we believe our results are noteworthy and could be important in guiding future studies. The strengths of our study are the large number of cases and the consistency in our data collection methods. We also identified many of the same risk factors for perioperative bleeding that previous studies have, suggesting credibility in our data collection methods and analysis.

To conclude, in a cohort of 507 patients who had thoracic aortic surgery with deep hypothermic circulatory arrest we found that the relationship between the percentage of CPB time under deep hypothermia and perioperative bleeding was generally dependent on total CPB time. For surgeries with short CPB times (120 to 180 minutes), prolonged deep hypothermia was associated with increased postoperative bleeding, estimated by increased RBC transfusion. For cases with long CPB times (300 to 360 minutes), deep hypothermia proportion had no association with postoperative bleeding. Future prospective randomized studies are needed to determine optimal temperature management during thoracic aortic surgery, which balances the risk of perioperative bleeding against the risk of neurologic injury.